Abstract
Mitogen-activated protein kinase (MAPK) signaling is involved in a variety of cellular functions. MAPK-dependent functions rely on phosphorylation of target proteins such as mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 participates in the early gene expression and in the production of pro- and anti-inflammatory cytokines. However, the role of MSK1 in neutrophil recruitment remains elusive. Here, we show that chemokine macrophage inflammatory protein-2 (CXCL2) enhances neutrophil MSK1 expression. Using intravital microscopy and time-lapsed video analysis of cremasteric microvasculature in mice, we studied the effect of pharmacological suppression of MSK1 by SB-747651A on CXCL2-elicited neutrophil recruitment. SB-747651A treatment enhanced CXCL2-induced neutrophil adhesion while temporally attenuating neutrophil emigration. CXCL2-induced intraluminal crawling was reduced following SB-747651A treatment. Fluorescence-activated cell sorting analysis of integrin expression revealed that SB-747651A treatment attenuated neutrophil integrin αMβ2 (Mac-1) expression following CXCL2 stimulation. Both the transmigration time and detachment time of neutrophils from the venule were increased following SB-747651A treatment. It also decreased the velocity of neutrophil migration in cremasteric tissue in CXCL2 chemotactic gradient. SB-747651A treatment enhanced the extravasation of neutrophils in mouse peritoneal cavity not at 1–2 h but at 3–4 h following CXCL2 stimulation. Collectively, our data suggest that inhibition of MSK1 by SB-747651A treatment affects CXCL2-induced neutrophil recruitment by modulating various steps of the recruitment cascade in vivo.
Highlights
During acute inflammation, neutrophils are recruited to the afflicted site by a well-defined and dynamic multi-step process that is regulated by a myriad of molecules and signaling cascades elicited by the cross-talk between neutrophils and endothelium [1,2]
Neutrophil-endothelial cell interactions during acute inflammation generate molecular signals that are decisive in the recruitment of neutrophils to the site of inflammation
The present study discloses the effect of pharmacological inhibition of mitogenand stress-activated protein kinase 1 (MSK1) on different steps of chemokine CXC chemokines such as macrophage inflammatory protein-2 (CXCL2)-induced neutrophil recruitment
Summary
Neutrophils are recruited to the afflicted site by a well-defined and dynamic multi-step process that is regulated by a myriad of molecules and signaling cascades elicited by the cross-talk between neutrophils and endothelium [1,2]. Signaling mechanisms that regulate different steps of neutrophil recruitment such as intraluminal crawling and subsequent transendothelial migration of neutrophils are not completely understood. MMiittooggeenn--aaccttiivvaatteedd pprrootteeiinn kkiinnaasseess ((MMAAPPKKss)) aarree iinnvvoollvveedd iinn aa wwiiddee vvaarriieettyy ooff cceelllluullaarr ffuunnccttiioonnss,, ssuucchh aass ddififfeferreennttiiaattiioonn,, ssuurrvviivvaall aanndd aappooppttoossiiss [[66,7,7]]. TThheeyy aarree kknnoowwnn ttoo ppaarrttiicciippaattee iinn tthhee ppaatthhoopphhyyssiioollooggyy ooff nneeuurroonnaall aanndd iinnffllaammmmaatotoryryddisieseaasesses[7[,78,]8.].MMAPAKP-Kde-dpeenpdenendtenfut nfcutniocntisonreslyreolyn opnhopshpohsoprhyolraytiloantioonf otafrtgaergt eptrportoeitneisnssuscuhchasasththeecclolosseelylyrreelalatteeddmmiittooggeenn-- aanndd ssttrreessss--aaccttiivvaatteedd pprrootteeiinn kkiinnaasseess MMSSKK11 aanndd MMSSKK22 [[99]]. FFiirrsstt,, wwee eexxaammiinneedd wwhheetthheerr tthhee ttrreeaattmmeenntt ooff nneeuuttrroopphhiillss wwiitthh CCXXCC cchheemmookkiinnee CCXXCCLL22 aaffffeeccttss. AAss sshhoowwnn iinn FFiigguurree 11,, ttrreeaattmmeenntt ooff mmoouussee bboonnee mmaarrrrooww nneeuuttrroopphhiillss wwiitthh. EEffffeecctt ooff SSBB--774477665511AA oonn CCXXCCLL22--iinndduucceedd nneeuuttrroopphhiill aaddhheessiioonn aanndd eemmiiggrraattiioonn.. TThheessee ddaattaa ssuuggggeesstt tthhaatt SSBB--774477665511AA ttrreeaattmmeenntt tthhwwaarrttss tthhee iinnttrraalluummiinnaall ccrraawwlliinngg ooff aaddhheerreenntt nneeuuttrroopphhiillss ttoo ooppttiimmaall ssiitteess ooff eemmiiggrraattiioonn. S that regulate transendothelial migration of neutrophils in response to CXCL2 chemotactic gradient. TThhee pprreesseenntt ssttuuddyy ddiisscclloosseess tthhee eeffffeecctt ooff pphhaarrmmaaccoollooggiiccaall iinnhhiibbiittiioonn ooff MMSSKK11 oonn ddiiffffeerreenntt sstteeppss ooff cchheemmookkiinnee CCXXCCLL22--
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